Epicenters of opioid misuse and related harms (e.g., HCV, overdose, HIV) are expanding from cities to rural areas in the US. These seismic epidemiologic shifts are crises that rural public health systems have yet to meet, and a wide ?implementation chasm? exists for drug-related health services in rural areas. Kentucky ? a predominately rural state at the forefront of these drug-related epidemics ? is starting to close this chasm by mounting an unprecedented expansion of syringe service programs (SSPs). Between 2015 and 2018, the number of legal SSPs operating in Kentucky surged from 0 to 40. This Kentucky expansion is part of a broader trend in the Appalachian region and other rural areas. This expansion represents a ?scale out? that takes SSPs to implementation contexts that differ qualitatively from their urban origins. Rural areas may present a constellation of barriers and facilitators to SSP adoption, fidelity, and sustainment that differ from those in cities. Cost, for example, may be a more significant barrier to adoption, fidelity, and sustainment in rural areas, where budgets are far more constrained. SSP staff may generate novel ways to implement core components that suit rural contexts, and SSP impact on risk behaviors and service use among clients may also be different in rural areas (e.g., transportation barriers and the paucity of local services may limit successful linkage to other services). Notably, little research has explored these possibilities: a recent Medline search using variants of the terms ?SSP,? ?rural,? and ?implementation science? identified no articles. The proposed study is a first step toward establishing the next generation of implementation science to enhance the effectiveness of this new wave of rural SSPs. Guided by the Consolidated Framework for Implementation Research, we will use a qualitative, multiple case study design to study SSPs that recently opened in 7 rural Kentucky counties to (1) Identify perceived barriers and facilitators in the rural implementation context to adopting and sustaining SSPs, and explore strategies to overcome barriers to adoption and sustainment. (2) Analyze the extent to which SSPs are faithful to established core components; identify emerging novel approaches to implementing core components that these SSPs may have innovated; and examine the processes through which select, salient features of the implementation context may have influenced this fidelity and innovation. (3) Explore PWID perceptions of whether and how SSP core components influence HIV, HCV, and overdose risk behaviors and drug-related health service use among SSP clients and other local PWID. This is a supplement to ?CARE2HOPE? (DA044798). Led by Drs. Young and Cooper, CARE2HOPE is designed to build evidence- based interventions (EBIs) for epidemics of opioid misuse and related harms in 12 rural Kentucky counties at an epicenter of these intertwined national crises. Several CARE2HOPE counties are considering enhancing SSPs as part of their EBI. This supplement will help identify barriers to SSP fidelity or sustainment that they could address. It will also generate hypotheses for a new line of high-impact rural SSP implementation science.